tbuckley/cabot-search huggingface dataset:
Potential Interactions When Prescribing SGLT2 Inhibitors and Intravenous Iron in Combination in Heart Failure
Authors: Milton Packer
Journal: JACC Heart Failure (2022)

In patients with heart failure, sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to decrease hepcidin and ferritin and increase transferrin receptor protein, changes that are typically indicative of worsening absolute iron deficiency, as would be seen with poor dietary intake or gastrointestinal bleeding, neither of which is provoked by SGLT2 inhibitors. Therefore, 2 alternative conceptual frameworks may explain the observed pattern of changes in iron homeostasis proteins. According to the "cytosolic iron depletion hypothesis," the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor is related to a decline in cytosolic Fe2+ that occurs after drug-induced erythropoietin-related increase in iron use. Erythropoietin-mimetics (eg, darbepoietin) elicit this type of iron-deficiency pattern of response, and it is typically accompanied by erythropoietin resistance that is alleviated by intravenous iron supplementation. In contrast, according to the "cytosolic iron repletion hypothesis," the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor represents a direct action of these drugs: 1) to reverse inflammation-related increases in hepcidin and ferritin, and, thus, alleviate functional blocks on iron utilization; and 2) to increase in sirtuin-1 signaling, which suppresses hepcidin, accelerates the degradation of ferritin, and up-regulates transferrin receptor protein. Through either or both mechanisms, direct suppression of hepcidin and ferritin would be expected to increase cytosolic Fe2+, thus allowing an unattenuated erythrocytic response to erythropoietin without the need for intravenous iron supplementation. The totality of clinical evidence supports the "cytosolic iron repletion hypothesis" because SGLT2 inhibitors elicit a full and sustained erythrocytosis in response to erythropoietin, even in overtly iron-deficient patients and in the absence of intravenous iron therapy. Therefore, the emergence of an iron-deficiency pattern of response during SGLT2 inhibition does not reflect worsening iron stores that are in need of replenishment, but instead, represents potential alleviation of a state of inflammation-related functional iron deficiency that is commonly seen in patients with chronic heart failure. Treatment with intravenous iron may be unnecessary and theoretically deleterious.
Size optimization of carfilzomib nanocrystals for systemic delivery to solid tumors
Authors: Hytham H. Gadalla, Seongsoo Lee, Hyungjun Kim, Abigail T. Armstrong, Dina Fathalla, Fawzia Habib, Hyunyoung Jeong, Wooin Lee, Yoon Yeo
Journal: Journal of Controlled Release (2022)
A Pt(IV)-conjugated brain penetrant macrocyclic peptide shows pre-clinical efficacy in glioblastoma
Authors: J.L. Jimenez-Macias, Y.-C. Lee, E. Miller, T. Finkelberg, M. Zdioruk, G. Berger, C.E. Farquhar, M.O. Nowicki, C.-F. Cho, B.I. Fedeles, A. Loas, B.L. Pentelute, S.E. Lawler
Journal: Journal of Controlled Release (2022)
Duration of Device-Based Fever Prevention after Cardiac Arrest
Authors: Christian Hassager, Henrik Schmidt, Jacob E. Møller, Johannes Grand, Simon Mølstrøm, Rasmus P. Beske, Søren Boesgaard, Britt Borregaard, Ditte Bekker-Jensen, Jordi S. Dahl, Martin S. Frydland, Dan E. Høfsten, Yusuf A. Isse, Jakob Josiassen, Vibeke R. Lind Jørgensen, Daniel Kondziella, Matias G. Lindholm, Emil Moser, Benjamin C. Nyholm, Laust E.R. Obling, Laura Sarkisian, Frederik T. Søndergaard, Jakob H. Thomsen, Jens J. Thune, Søren Venø, Sebastian C. Wiberg, Matilde Winther-Jensen, Martin A.S. Meyer, Jesper Kjaergaard
Journal: New England Journal of Medicine (2022)

Guidelines recommend active fever prevention for 72 hours after cardiac arrest. Data from randomized clinical trials of this intervention have been lacking.
Defibrillation Strategies for Refractory Ventricular Fibrillation
Authors: Sheldon Cheskes, P. Richard Verbeek, Ian R. Drennan, Shelley L. McLeod, Linda Turner, Ruxandra Pinto, Michael Feldman, Matthew Davis, Christian Vaillancourt, Laurie J. Morrison, Paul Dorian, Damon C. Scales
Journal: New England Journal of Medicine (2022)

Despite advances in defibrillation technology, shock-refractory ventricular fibrillation remains common during out-of-hospital cardiac arrest. Double sequential external defibrillation (DSED; rapid sequential shocks from two defibrillators) and vector-change (VC) defibrillation (switching defibrillation pads to an anterior–posterior position) have been proposed as defibrillation strategies to improve outcomes in patients with refractory ventricular fibrillation.
If the Fates Allow: The Zero-Sum Game of ISCHEMIA-EXTEND
Authors: Steven M. Bradley, Ty J. Gluckman
Journal: Circulation (2022)

ccording to the ancient Greeks, the lives of the gods and mortals were immutably determined by 3 Fates: sisters Clotho, who spins the thread of life; Lachesis, who assigns each their destiny; and Atropos, whose scissors snip the thread of life at its end.Among the goals of medicine is to bend the will of fate by forestalling death.The extent to which coronary revascularization alters the fate of patients with stable ischemic heart disease (IHD) remains an important question.
Comparative Effects of Low-Dose Rosuvastatin, Placebo, and Dietary Supplements on Lipids and Inflammatory Biomarkers
Authors: Luke J. Laffin, Dennis Bruemmer, Michelle Garcia, Danielle M. Brennan, Ellen McErlean, Douglas S. Jacoby, Erin D. Michos, Paul M Ridker, Tracy Y. Wang, Karol E. Watson, Howard G. Hutchinson, Steven E. Nissen
Journal: Journal of the American College of Cardiology (2022)

Supplements are commonly used by individuals with indications for lipid-lowering therapy, but evidence of their effectiveness to lower low-density lipoprotein cholesterol (LDL-C) is lacking, particularly when compared with statins. The trial objective was to compare the efficacy of a low-dose statin with placebo and 6 common supplements in impacting lipid and inflammatory biomarkers. This was a single-center, prospective, randomized, single-blind clinical trial among adults with no history of atherosclerotic cardiovascular disease (ASCVD), an LDL-C of 70 to 189 mg/dL, and an increased 10-year risk of ASCVD. Participants were randomized to rosuvastatin 5 mg daily, placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice. The primary endpoint was the percent change in LDL-C from baseline for rosuvastatin 5 mg daily compared with placebo and each supplement after 28 days. The primary endpoint was evaluated in a hierarchical fashion with rosuvastatin first compared with placebo, then each supplement in a prespecified order using analysis of covariance. A total of 190 participants completed the study. The percent LDL-C reduction with rosuvastatin was greater than all supplements and placebo (P < 0.001). The difference in LDL-C reduction with rosuvastatin compared with placebo was −35.2% (95% CI: −41.3% to −29.1%; P < 0.001). None of the dietary supplements demonstrated a significant decrease in LDL-C compared with placebo. Adverse event rates were similar across study groups. Among individuals with increased 10-year risk for ASCVD, rosuvastatin 5 mg daily lowered LDL-C significantly more than placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice. (Supplements, Placebo, or Rosuvastatin Study [SPORT]; NCT04846231)
Indobufen or Aspirin on Top of Clopidogrel After Coronary Drug-Eluting Stent Implantation (OPTION): A Randomized, Open-Label, End Point–Blinded, Noninferiority Trial
Authors: Hongyi Wu, Lili Xu, Xin Zhao, Huanyi Zhang, Kang Cheng, Xiaoyan Wang, Manhua Chen, Guangping Li, Jiangnan Huang, Jun Lan, Guanghe Wei, Chi Zhang, Yinman Wang, Juying Qian, Junbo Ge
Journal: Circulation (2022)

Background: Dual antiplatelet therapy (DAPT) with aspirin as a background therapy has become the standard care after percutaneous coronary intervention. However, some adverse noncardiac effects limited the use of aspirin in clinical practice. Thus, evaluation of pharmacological alternatives to aspirin is attractive. Previous data indicated that indobufen could lessen the unwanted side effects of aspirin while retaining the antithrombotic efficacy, but its combination with a P2Y 12 inhibitor still lacks randomized clinical trial evidence. Methods: In this randomized, open-label, noninferiority trial, patients with negative cardiac troponin undergoing coronary drug-eluting stent implantation were randomly assigned in a 1:1 ratio to receive either indobufen-based DAPT (indobufen 100 mg twice a day plus clopidogrel 75 mg/d for 12 months) or conventional DAPT (aspirin 100 mg/d plus clopidogrel 75 mg/d for 12 months). The primary end point was a 1-year composite of cardiovascular death, nonfatal myocardial infarction, ischemic stroke, definite or probable stent thrombosis, or Bleeding Academic Research Consortium criteria type 2, 3, or 5 bleeding. The end points were adjudicated by an independent Clinical Event Committee. Results: Between January 11, 2018, and October 12, 2020, 4551 patients were randomized in 103 cardiovascular centers: 2258 patients to the indobufen-based DAPT group and 2293 to the conventional DAPT group. The primary end point occurred in 101 patients (4.47%) in the indobufen-based DAPT group and 140 patients (6.11%) in the conventional DAPT group (absolute difference, −1.63%; P noninferiority &lt;0.001; hazard ratio, 0.73 [95% CI, 0.56–0.94]; P =0.015). Cardiovascular death, nonfatal myocardial infarction, ischemic stroke, and stent thrombosis were observed in 0.13%, 0.40%, 0.80%, and 0.22% of patients in the indobufen-based DAPT group and 0.17%, 0.44%, 0.83%, and 0.17% of patients in the conventional DAPT group (all P &gt;0.05). The occurrence of Bleeding Academic Research Consortium criteria type 2, 3, or 5 bleeding events was lower in the indobufen-based DAPT group compared with the conventional DAPT group (2.97% versus 4.71%; hazard ratio, 0.63 [95% CI, 0.46–0.85]; P =0.002), with the main decrease in type 2 bleeding (1.68% versus 3.49%; hazard ratio, 0.48 [95% CI, 0.33–0.70]; P &lt;0.001). Conclusions: In Chinese patients with negative cardiac troponin undergoing drug-eluting stent implantation, indobufen plus clopidogrel DAPT compared with aspirin plus clopidogrel DAPT significantly reduced the risk of 1-year net clinical outcomes, which was driven mainly by a reduction in bleeding events without an increase in ischemic events. Registration: URL: https://www.chictr.org.cn ; Unique identifier: ChiCTR-IIR-17013505.
Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials
Authors: Colin Baigent, JonathanR. Emberson, Richard Haynes, William G. Herrington, Parminder Judge, Martin J. Landray, Kaitlin J. Mayne, Sarah Y.A. Ng, David Preiss, Alistair J. Roddick, Natalie Staplin, Doreen Zhu, Stefan D. Anker, Deepak L. Bhatt, Martina Brueckmann, Javed Butler, David Z.I. Cherney, Jennifer B. Green, Sibylle J. Hauske, Richard Haynes, Hiddo J.L. Heerspink, William G. Herrington, Silvio E. Inzucchi, Meg J. Jardine, Chih-Chin Liu, Kenneth W. Mahaffey, Finnian R. McCausland, Darren K. McGuire, John J.V. McMurray, Bruce Neal, Brendon L. Neuen, Milton Packer, Vlado Perkovic, Marc S. Sabatine, Scott D. Solomon, Muthiah Vaduganathan, Christoph Wanner, David C. Wheeler, Stephen D. Wiviott, Faiez Zannad
Journal: The Lancet (2022)
Treatment Time and In-Hospital Mortality Among Patients With ST-Segment Elevation Myocardial Infarction, 2018-2021
Authors: James G. Jollis, Christopher B. Granger, Jessica K. Zègre-Hemsey, Timothy D. Henry, Abhinav Goyal, Jacqueline E. Tamis-Holland, Mayme Lou Roettig, Murtuza J. Ali, William J. French, Ram Poudel, Juan Zhao, R. Harper Stone, Alice K. Jacobs
Journal: JAMA (2022)

Recognizing the association between timely treatment and less myocardial injury for patients with ST-segment elevation myocardial infarction (STEMI), US national guidelines recommend specific treatment-time goals.To describe these process measures and outcomes for a recent cohort of patients.Cross-sectional study of a diagnosis-based registry between the second quarter of 2018 and the third quarter of 2021 for 114 871 patients with STEMI treated at 648 hospitals in the Get With The Guidelines-Coronary Artery Disease registry.STEMI or STEMI equivalent.Treatment times, in-hospital mortality, and adherence to system goals (75% treated ≤90 minutes of first medical contact if the first hospital is percutaneous coronary intervention [PCI]-capable and ≤120 minutes if patients require transfer to a PCI-capable hospital).In the study population, median age was 63 (IQR, 54-72) years, 71% were men, and 29% were women. Median time from symptom onset to PCI was 148 minutes (IQR, 111-226) for patients presenting to PCI-capable hospitals by emergency medical service, 195 minutes (IQR, 127-349) for patients walking in, and 240 minutes (IQR, 166-402) for patients transferred from another hospital. Adjusted in-hospital mortality was lower for those treated within target times vs beyond time goals for patients transported via emergency medical services (first medical contact to laboratory activation ≤20 minutes [in-hospital mortality, 3.6 vs 9.2] adjusted OR, 0.54 [95% CI, 0.48-0.60], and first medical contact to device ≤90 minutes [in-hospital mortality, 3.3 vs 12.1] adjusted OR, 0.40 [95% CI, 0.36-0.44]), walk-in patients (hospital arrival to device ≤90 minutes [in-hospital mortality, 1.8 vs 4.7] adjusted OR, 0.47 [95% CI, 0.40-0.55]), and transferred patients (door-in to door-out time <30 minutes [in-hospital mortality, 2.9 vs 6.4] adjusted OR, 0.51 [95% CI, 0.32-0.78], and first hospital arrival to device ≤120 minutes [in-hospital mortality, 4.3 vs 14.2] adjusted OR, 0.44 [95% CI, 0.26-0.71]). Regardless of mode of presentation, system goals were not met in most quarters, with the most delayed system performance among patients requiring interhospital transfer (17% treated ≤120 minutes).This study of patients with STEMI included in a US national registry provides information on changes in process and outcomes between 2018 and 2021.
Deciphering the impact of genetic variation on human polyadenylation using APARENT2
Authors: Johannes Linder, Samantha E. Koplik, Anshul Kundaje, Georg Seelig
Journal: Genome biology (2022)

Abstract Background 3′-end processing by cleavage and polyadenylation is an important and finely tuned regulatory process during mRNA maturation. Numerous genetic variants are known to cause or contribute to human disorders by disrupting the cis-regulatory code of polyadenylation signals. Yet, due to the complexity of this code, variant interpretation remains challenging. Results We introduce a residual neural network model, APARENT2 , that can infer 3′-cleavage and polyadenylation from DNA sequence more accurately than any previous model. This model generalizes to the case of alternative polyadenylation (APA) for a variable number of polyadenylation signals. We demonstrate APARENT2’s performance on several variant datasets, including functional reporter data and human 3′ aQTLs from GTEx. We apply neural network interpretation methods to gain insights into disrupted or protective higher-order features of polyadenylation. We fine-tune APARENT2 on human tissue-resolved transcriptomic data to elucidate tissue-specific variant effects. By combining APARENT2 with models of mRNA stability, we extend aQTL effect size predictions to the entire 3′ untranslated region. Finally, we perform in silico saturation mutagenesis of all human polyadenylation signals and compare the predicted effects of $${&gt;}43$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mo>&gt;</mml:mo><mml:mn>43</mml:mn></mml:mrow></mml:math> million variants against gnomAD. While loss-of-function variants were generally selected against, we also find specific clinical conditions linked to gain-of-function mutations. For example, we detect an association between gain-of-function mutations in the 3′-end and autism spectrum disorder. To experimentally validate APARENT2’s predictions, we assayed clinically relevant variants in multiple cell lines, including microglia-derived cells. Conclusions A sequence-to-function model based on deep residual learning enables accurate functional interpretation of genetic variants in polyadenylation signals and, when coupled with large human variation databases, elucidates the link between functional 3′-end mutations and human health.
Dose-Blinded Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy: Outcomes Through 32 Weeks
Authors: Milind Y. Desai, Anjali Owens, Jeffrey B. Geske, Kathy Wolski, Sara Saberi, Andrew Wang, Mark Sherrid, Paul C. Cremer, Srihari S. Naidu, Nicholas G. Smedira, Hartzell Schaff, Ellen McErlean, Christina Sewell, Aarthi Balasubramanyam, Kathy Lampl, Amy J. Sehnert, Steven E. Nissen
Journal: Circulation (2022)

Septal reduction therapy (SRT) in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy (oHCM) is associated with variable morbidity and mortality. The VALOR-HCM trial (A Study to Evaluate Mavacamten in Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) examined the effect of mavacamten on the need for SRT through week 32 in oHCM.A double-blind randomized placebo-controlled multicenter trial at 19 US sites included patients with oHCM on maximal tolerated medical therapy referred for SRT with left ventricular outflow tract gradient ≥50 mm Hg at rest or provocation (enrollment, July 2020-October 2021). The group initially randomized to mavacamten continued the drug for 32 weeks, and the placebo group crossed over to dose-blinded mavacamten from week 16 to week 32. Dose titrations were based on investigator-blinded echocardiographic assessment of left ventricular outflow tract gradient and left ventricular ejection fraction. The principal end point was the proportion of patients proceeding with SRT or remaining guideline eligible at 32 weeks in both treatment groups.From the 112 randomized patients with oHCM, 108 (mean age, 60.3 years; 50% men; 94% in New York Heart Association class III/IV) qualified for week 32 evaluation (56 in the original mavacamten group and 52 in the placebo cross-over group). After 32 weeks, 6 of 56 patients (10.7%) in the original mavacamten group and 7 of 52 patients (13.5%) in the placebo cross-over group met SRT guideline criteria or elected to undergo SRT. After 32 weeks, a sustained reduction in resting left ventricular outflow tract gradient (-33.0 mm Hg [95% CI, -41.1 to -24.9]) and Valsalva left ventricular outflow tract gradient (-43.0 mm Hg [95% CI, -52.1 to -33.9]) was observed in the original mavacamten group. A similar reduction in resting (-33.7 mm Hg [95% CI, -42.2 to -25.2]) and Valsalva (-52.9 mm Hg [95% CI, -63.2 to -42.6]) gradients was quantified in the cross-over group after 16 weeks of mavacamten. After 32 weeks, improvement by ≥1 New York Heart Association class was observed in 48 of 53 patients (90.6%) in the original mavacamten group and 35 of 50 patients (70%) after 16 weeks in the cross-over group.In severely symptomatic patients with oHCM, 32 weeks of mavacamten treatment showed sustained reduction in the proportion proceeding to SRT or remaining guideline eligible, with similar effects observed in patients who crossed over from placebo after 16 weeks.URL: https://www.gov; Unique identifier: NCT04349072.
Decongestion With Acetazolamide in Acute Decompensated Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Prespecified Analysis From the ADVOR Trial
Authors: Pieter Martens, Jeroen Dauw, Frederik H. Verbrugge, Petra Nijst, Evelyne Meekers, Silvio Nunes Augusto, Jozine M. Ter Maaten, Kevin Damman, Alexandre Mebazaa, Gerasimos Filippatos, Frank Ruschitzka, W.H. Wilson Tang, Matthias Dupont, Wilfried Mullens
Journal: Circulation (2022)

Background: Acetazolamide inhibits proximal tubular sodium reabsorption and improved decongestion in the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial. It remains unclear whether the decongestive effects of acetazolamide differ across the spectrum of left ventricular ejection fraction (LVEF). Methods: This is a prespecified analysis of the randomized, double-blind, placebo-controlled ADVOR trial that enrolled 519 patients with acute heart failure (HF), clinical signs of volume overload (eg, edema, pleural effusion, or ascites), NTproBNP (N-terminal pro-B-type natriuretic peptide) &gt;1000 ng/L, or BNP (B-type natriuretic peptide) &gt;250 ng/mL to receive intravenous acetazolamide (500 mg once daily) or placebo in addition to standardized intravenous loop diuretics (twice that of the oral home maintenance dose). Randomization was stratified according to LVEF (≤40% or &gt;40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload within 3 days from randomization without the need for mandatory escalation of decongestive therapy because of poor urine output. Results: Median LVEF was 45% (25th to 75th percentile; 30% to 55%), and 43% had an LVEF ≤40%. Patients with lower LVEF were younger and more likely to be male with a higher prevalence of ischemic heart disease, higher NTproBNP, less atrial fibrillation, and lower estimated glomerular filtration rate. No interaction on the overall beneficial treatment effect of acetazolamide to the primary end point of successful decongestion (OR, 1.77 [95% CI, 1.18-2.63]; P =0.005; all P values for interaction &gt;0.401) was found when LVEF was assessed per randomization stratum (≤40% or &gt;40%), or as HF with reduced ejection fraction, HF with mildly reduced ejection fraction, and HF with preserved ejection fraction, or on a continuous scale. Acetazolamide resulted in improved diuretic response measured by higher cumulative diuresis and natriuresis and shortened length of stay without treatment effect modification by baseline LVEF (all P values for interaction &gt;0.160). Conclusions: When added to treatment with loop diuretics in patients with acute decompensated HF, acetazolamide improves the incidence of successful decongestion and diuretic response, and shortens length of stay without treatment effect modification by baseline LVEF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03505788.
Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH
Authors: Vlad Ratziu, Stephen A. Harrison, Véronique Loustaud-Ratti, Christophe Bureau, Eric Lawitz, Manal Abdelmalek, Naim Alkhouri, Sven Francque, Hugo Girma, Raphaël Darteil, Harold Couchoux, Myles Wolf, Arun Sanyal, Jacky Vonderscher, Pietro Scalfaro
Journal: Journal of Hepatology (2022)
CXCR4-targeted nitric oxide nanoparticles deliver PD-L1 siRNA for immunotherapy against glioblastoma
Authors: Hsin-Tzu Hsieh, Hsi-Chien Huang, Chieh-Wei Chung, Cheng-Chin Chiang, Tiffaney Hsia, Hsin-Fang Wu, Rui-Lin Huang, Chi-Shiun Chiang, Jane Wang, Tsai-Te Lu, Yunching Chen
Journal: Journal of Controlled Release (2022)